Basically substituted 1,4-dihydro-2H-isoquinoline derivatives and process for preparing them

ABSTRACT

1,4-Dihydro-2H-isoquinoline derivatives of the general formula I ##SPC1## 
     in which 
     R 1  represents hydrogen or straight chain or branched alkyl of 1 to 6 carbon atoms, 
     R 2  represents low molecular dialkylaminoalkyl, in which both alkyl groups of the dialkylamino group together with the nitrogen atom may also form a 5-, 6- or 7-membered saturated ring in which one carbon atom may be substituted by an oxygen atom, a sulfur atom or another nitrogen atom which may be substituted by hydrogen, C 1  -C 4  -alkyl or phenyl, or R 1  and R 2  together may form a 5- or 6-membered saturated ring containing 1 nitrogen atom, 
     R 3  represents phenyl which may be mono- or di-substituted by halogen, nitro, amino or sulfamoyl, or acylamino or alkyl each containing 1 to 4 carbon atoms, or pyridyl 
     R 4  and 
     R 5 , which may identical or different, represent hydrogen or alkoxy of 1 to 4 carbon atoms, and 
     X represent oxygen or sulfur, 
     Their physiologically tolerated salts, process for preparing them. The compounds are active on the coronary circulation and are distinguished in particular by an anti-arrhythmic action and may, therefore, be used in the treatment of disorders of the heart rhythm.

1-Phenyl-1,4-dihydro-2H-isoquinoline-3-ones which are unsubstituted ordi-methyl substituted in the 4-position are known from Acad. Sci. Hung.60, (1969), page 177, and 1-alkyl-1,4-dihydro-2H-isoquinoline-3-oneswhich are unsubstituted or di-lower alkyl substituted in the 4-positionare known from U.S. Pat. No. 3,480,634.1-Phenyl-1,4-dihydro-2H-isoquinoline-3-ones which are alkyl-substitutedin the 4-position and their anticonvulsive action are described inBelgian Patent No. 784 037.

Now, we have found that 1,4-dihydro-2H-isoquinoline-3-ones which carrybasic substituents in the 4-position and phenyl or pyridyl substituentsin the 1-position have an action on the coronary circulation.

Thus, the present invention relates to 1,4-dihydro-2H-isoquinolinederivatives of the general formula I ##SPC2##

in which

R¹ represents hydrogen or straight chain or branched alkyl of 1 to 6carbon atoms,

R² represents low molecular dialkylaminoalkyl, in which both alkylgroups of the dialkylamino group together with the nitrogen atom mayalso form a 5-, 6- or 7-membered saturated ring in which one carbon atommay be substituted by an oxygen atom, a sulfur atom or another nitrogenatom which may be substituted by hydrogen, C₁ -C₄ -alkyl or phenyl, orR¹ and R² together may form a 5- or 6-membered saturated ring containing1nitrogen atom,

R³ represents phenyl which may be mono- or di-substituted by halogen,nitro, amino or sulfamoyl, or acylamino or alkyl each containing 1 to 4carbon atoms, or pyridyl,

R⁴ and

R⁵, which may identical or different, represent hydrogen or alkoxy of 1to 4 carbon atoms, and

X represents oxygen or sulfur, and to their physiologically toleratedsalts.

Among the radicals mentioned above, R¹ preferably represents hydrogen,R² preferably represents a dialkylaminoalkyl group of the formula##EQU1## in which n preferably represents the number 2 or 3 and Z and Yare identical hydrocarbon radicals of 1 to 4 carbon atoms or Z and Ytogether with the nitrogen atom form a 5- or 6-membered ring,furthermore the morpholino-ethyl radical, R³ represents a phenyl ringmono- or di-substituted by chlorine, amino or sulfamyl, or the pyridineradical, and R⁴ and R⁵ represent identical substituents, hydrogen ormethoxy groups being preferred.

Furthermore, the present invention relates to a process for preparingthe above-specified compounds and to pharmaceutical preparationsproduced with these compounds.

Thus, the process for preparing the compounds of the invention comprises

a. reacting compounds of the formula II ##SPC3##

in which R¹, R², R⁴ and R⁵ have the meanings given for formula I and Qrepresents a --CN or --CXNH₂ groups, in which X is oxygen or sulfur,with an aldehyde of the formula III

    R.sup.3 - CHO                                              (III)

in which R³ has the meaning given for formula I, to compounds of theformula I, or

b. hydrogenating compounds of the formula IV ##SPC4##

in which R¹ to R⁵ and X have the meanings given for formula I, or

c. subjecting oximes of the formula V ##SPC5##

in which R¹ to R⁵ have the meanings given for formula I, or theirO-derivatives, to a Beckmann rearrangement, or

d. reacting compounds of the formula VI ##SPC6##

in which R¹ to R⁵ have the meanings given for formula I, with ammonia orsalts thereof, or

e. cyclizing α-hydroxyacetic acid amides or -thioamides of the formulaVII ##SPC7##

in which R¹ to R⁵ and X have the meanings given for formula I, or

f. cyclizing amino-acid- or thioamino-acid derivatives of the formulaVIII ##SPC8##

in which R¹ to R⁵ have the meanings given for formula I and Y representsa carboxyl or thio-carboxyl group, or the derivatives thereof, orhydroxy-carboxylic acid amides or hydroxy-thiocarboxylic acid amines ofthe formula IX ##SPC9##

in which R¹ to R⁵ and X have the meanings given for formula I, or

g. cyclizing metal organyles of the formula X ##SPC10##

in which R¹ to R⁵ and X have the meanings given for formula I, Urepresents oxygen, sulfur or the NH-group, Z represents alkyl or aryl,Me represents a mono-valent alkali metal, with separation of Me U, Z, or

h. cyclizing benzylidene-bisphenyl-acetic acid amides orbenzylidene-bis-thiophenylacetic acid amides of the formula XI ##SPC11##

in which R¹ to R⁵ and X have the meanings given for formula I, withseparation of a phenyl- or thio-phenylacetic acid amide, or

i. subsequently introducing into compounds of the formula I in which R¹and/or R² represent hydrogen, the substituents R¹ and/or R² byalkylation, or

k. reacting compounds of the formula XII ##SPC12##

in which X, R¹, R³, R⁴ and R⁵ have the meanings given for formula I andin which n is a number from 1 to 4 and Y represents a substituent whichis replaceable by a secondary amine, with a secondary amine, or

1. subsequently substituting the amino group in a compound of theformula XIII ##SPC13##

in which R¹, R³ to R⁵ and X have the meanings given for formula I, and nis a number from 1 to 4, or

m. cyclizing a compound of the formula XIV ##SPC14##

in which X, R¹, R³, R⁴ and R⁵ have the meanings given for formula I, nis a number from 1 to 4, R⁷ and R⁸ represent low molecular alkyl and Yand Z represent the hydroxy, mercapto or amino group, or

n. cyclizing a compound of the formula XIV, in which X, R¹, R³, R⁴, R⁵,R⁷, R⁸ and n have the meanings given above and Y and Z represent aradical which may be substituted by ammonia, a primary amine, hydrogensulfide or water, with ammonia, a primary amine or by a treatment withwater or hydrogen sulfide, and, if desired, replacing oxygen in thereaction products by sulfur, or sulfur by oxygen in a known manner.

The benzyl-cyanides of the general formula II (Q = CN) may be prepared,for example by alkylation of the corresponding benzyl-cyanides with analkyl halide in the presence of sodium amide in an inert solvent, forexample according to the method described in Liebigs Annalen, Vol. 561(1949), page 52 et seq.

The benzyl-cyanides so obtained are reacted with an aldehyde (III) inthe presence of acid catalysts with or without a solvent. As catalysts,there may be used in particular mineral acids, for example sulfuricacid, hydrochloric acid and phosphoric acid, Lewis acids such as borontrifluoride and aluminum chloride, and phosphorus-oxychloride. Assolvents, there may be used, for example benzene, toluene, carbontetrachloride or trichloroethylene.

The reaction is carried out, for example according to the methoddescribed in Acta Chim. Acad. Sci. Hung. 60, page 177 (1969). Thus, bothreactants are reacted in phosphoric acid, the content of phosphoruspentoxide of which may vary between that of 85% phosphoric acid and thatof poly-phosphoric acid. The operation is carried out at temperatures inthe range of from room temperature to 150° C, a temperature of from 90°to 110° C being preferred.

The phosphoric acid preferably used in the reaction is most simplyprepared by adding 30 to 70 g of phosphorus pentoxide to 30 to 70 ml of85% phosphoric acid.

The reaction of the aldehydes III with phenylacetic acid amides of theformula II (Q = --CO-NH₂) is likewise carried out most advantageously inthe same manner.

The thioamides of the formula II (Q = --CSNH₂) are prepared according tothe usual methods from phenylacetic acid amides by exchange of theoxygen against the for sulfur. The condensation with an aldehyde of theformula III is effected under the same conditions as described above.

The starting compounds IV which are used in method b) are obtained, forexample according to the method described in J. Heterocyclic Chem. 1,(1970), page 615, by subjecting compounds of the formula XII to thereactions in the order indicated therein. ##SPC15##

By reaction with a Grignard reagent, there is obtained from XV thehydroxy compound XVI which is reacted with methanol/hydrochloric acid tothe methyl ether XVII.

After separation of methanol, there is obtained IV in which X = oxygen.The corresponding thio-compound is obtained by replacing the oxygen ofthe lactam group in a compound of formula XVII by sulfur in one of theusual ways and subsequently separating methanol as described above.

The reduction of IV to I may be carried out catalytically in thepresence of metal catalysts, for example Raney nickel or palladium blackin suitable solvents, for example alcohol or ether. Suitable complexhydrides may also be used for the reduction. The operation is carriedout, for example, with sodium boron hydride in solvents, for examplemethanol, dioxane or dimethoxyethane, at temperatures between roomtemperature and the boiling point of the solvent.

The oximes of the formula V required for method (c) are obtainedaccording to the method described in J. Chem. Soc. (C), page 2245(1970).

This method is started from suitably substituted indane-2-ones XVIII##SPC16##

in which R¹ to R⁵ have the meanings given above, which are reacted tothe oximes V in the usual manner.

As O-derivatives of the oximes, there may be used in particular themesylates or tosylates thereof, which are prepared in the usual way.

The Beckmann rearrangement according to method (c) is effected suitablyunder acidic conditions or, in the case of substituted oximes, alsounder alkaline conditions.

The compounds of the formula VI are obtained, for example, bycondensation of phenylacetic acid esters with aromatic aldehydes.##SPC17##

This is effected by reacting the two reactants, with or without asolvent, for example acetic acid or tetrahydrofurane, with acidcatalysts, for example sulfuric acid or hydrochloric acid, attemperatures between 25° C and 100° C. Compounds of the general formulaVI are then reacted according to (d) with ammonia or the salts thereof,with or without a solvent, for example alcohol, optionally at pressuresof up to 150 atmospheres gauge, at temperatures between 50° and 200° C,to compounds of the general formula I. Or, the process is carried outunder the conditions described in U.S. Pat. No. 3,480,634.

The reaction according to method (e) succeeds under the conditionsindicated for method (a).

Amino-acid derivatives VIII and hydroxycarboxylic acid derivatives IX,which can be obtained by one of the usual methods, may be cyclized withor without acid catalysts, for example sulfuric acid or phosphoric acid,or with or without dehydratating agents, for example acetic acidanhydride or thionyl chloride, with or without solvents, for exampleglacial acetic acid, alcohol or ether, at temperatures in the range offrom room temperature to the boiling temperature of the solvent.

When preparing the products of the invention according to method (g),the process is preferably started from derivatives of isocyanic acid orisothiocyanic acid, for example urethanes or thiourethanes of theformula XIX ##SPC18##

(x = o,s), which are reacted, for example with n-butyl-lithium to themetal organyles of the formula X.

Particularly suitable derivatives are the carbamic acid or thio-carbamicacid esters, in which X is oxygen or sulfur, U is oxygen and Z is lowmolecular alkyl, the thio- or di-thiocarbamic acid esters, in which X isoxygen or sulfur, U is sulfur and Z is lower alkyl or phenyl, and ureaderivatives or thiourea derivatives, in which U is the NH-group and Z islower alkyl or phenyl.

Cyclization of X to I is suitably carried out at elevated temperaturesin inert solvents, for example benzene, toluene, dimethoxyethane, atroom temperature up to the boiling temperature of the solvent.

During cyclization, UZ is split off.

In the reaction of compounds II with aromatic aldehydes III there mayform, under the conditions mentioned for method (a), the compounds ofthe formula XI as intermediate products, which, however, are notisolated, but pass into the compounds of the formula I with eliminationof a phenylacetic acid amide or thioamide.

The compounds of the general formula XI, which are used in method (h),may be prepared and isolated in another way. For this purpose, thecompounds II and the aldehyde III are heated with or without a solvent,for example alcohols, benzene, or chloroform, during which time thereaction water that has formed is continuously separated.

The compounds of the formula XI are converted into compounds of theformula I by acid catalysis, it being possible to work with a solvent,for example benzene, a halogenated hydrocarbon or an alcohol, or withoutsolvent, or to use polyphosphoric acid or other mineral acids, forexample hydrochloric acid or sulfuric acid, or Lewis acids, for exampleBF₃, or other acid catalysts, for example POCl₃.

The subsequent introduction of the substituents R¹ and/or R² into theisoquinoline molecule XX ##SPC19##

is carried out according to known methods, by protecting the amidefunction, for example with a suitable reagent such as chloroformic acidester under alkylating conditions, for example with alcoholate inalcohol or sodium amide in inert solvents, for example benzene (XXI).Then, the substituents R¹ and R² may be introduced into XXI ##SPC20##

by step-wise alkylation, for example with sodium amide in inertsolvents, for example benzene or toluene, it being without importancewhether the substitution is carried out first with R¹ or with R². Thefollowing hydrolysis and decarboxylation, for example by a treatmentwith acids or bases in water, alcohols or aqueous alcohols yields thecompounds of the formula I.

The reaction according to method (k), Y in XII preferably being ahalogen atom such as Cl or I, or another radical which is replaceable bya secondary amine, for example the tosyl or mesyl radical, is effectedin the presence of an excess of the secondary amine to be used, or, isthe secondary amine is added in stoichiometric amounts, with addition ofa base, preferably sodium hydroxide solution, aqueous sodium carbonatesolution, triethylamine or alcoholate, in suitable solvents, forexample, water, alcohols such as methanol or butanol, ethers such asdiethyl ether or dimethoxyethylene, aromatic or aliphatic, optionallyhalogenated hydrocarbons such as cyclohexane, chloroform, toluene orchlorobenzene, polar solvents such as dimethylsulfoxide ordimethylformamide or mixtures of the mentioned solvents, at atemperature between room temperature and the boiling temperature of thesolvent used.

Alkylation of a compound of the formula XIII according to method (1) maybe carried according to known methods, the alkylation with an alkylester of a mineral or organic acid, for example dimethyl- ordiethyl-sulfate or a benzenesulfonic acid alkyl ester being preferablyemployed (cf. Org. Synth. 44, 72 (1964), Pharm. Chem. J. 193, (1969)),or by subjecting a compound of the formula XII to a reaction with acorresponding alkyl compound while applying the conditions specified formethod (k). It is also possible to introduce the two alkyl radicalssuccessively. Thus, the amine may be reacted with an aldehyde or ketoneto a Schiff's base, the Schiff's base is alkylated and the ammonium saltis hydrogenated. It is suitable to work according to the methoddescribed in Chem. Inform. 16 - 258 (1973).

The compounds of the formula XIV are cyclized according to the usualmethods. The cyclization may be carried out in the presence of acatalyst, but also without catalyst. It may be carried out in an inertsolvent or without solvent. This is suitably done by keeping a compoundof the formula II in an inert solvent in the presence of an acidcatalyst, preferably boron trifluoride etherate or p-toluene-sulfonicacid until completion of the reaction at temperatures between 0° C andthe boiling temperature of the solvent used. As solvents, there may beused preferably ethers such as tetrahydrofurane, dimethoxyethane or,optionally also chlorinated aliphatic or aromatic hydrocarbons such ascyclohexane, methylene chloride, chlorobenzene or toluene.

If Y and/or Z represent the hydroxy group, the reaction water that hasformed is separated preferably by means of a water separator.

The reaction according to method (n), Y and Z in XIV preferably being ahalogen atom such as C1 or I, or another radical which is replaceable bya primary amine, for example the tosyl or mesyl radical, is carried outin the presence of an excess of the primary amine or water to be used,or if the reagent is used in a stoichiometric amount, with addition of abase such as, preferably sodium hydroxide solution, aqueous sodiumcarbonate solution, triethylamine or alcoholate in suitable solvents,for example water, alcohols such as methanol or butanol, ethers such asdiethyl ether or dimethoxyethylene, aromatic or aliphatic, optionallyhalogenated hydrocarbons such as cyclohexane, chloroform, toluene orchlorobenzene, polar solvents such as dimethyl-sulfoxide ordimethylformamide or mixtures of the mentioned solvents at a temperaturebetween room temperature and the boiling temperature of the solventused.

For converting the compounds of the formula I (X = O) into thecorresponding sulfur derivatives, known reactions are employed.Particularly suitable is the reaction with P₄ S₁₀ in pyridine or toluenewith or without the addition of an acid-binding agent, for example CaO,or I (X = O) is reacted with PC1₅ in pyridine, benzene or toluene to theimide-chloride which yields with H₂ S or a thio-urea, optionally afterhydrolysis of the intermediately formed isothiouronium salt, compoundsof the formula I (X = S).

For converting thioamides into the corresponding amides, known methodsare used. A reaction with an alkyl halide, which may also be substitutedbasically, is also suitable, in which the thione of the formula I reactsformally in its tautomeric imino form. The operation is carried outoptionally in the presence of a base, for example potassium carbonate,in an inert solvent such as benzene, toluene, xylene, acetone ormethylethyl ketone at elevated temperature, whereupon a S-alkyl compoundis obtained which is de-sulfurized with mineral acid, for examplehydrochloric acid, at elevated temperature. The thione of the formula Imay also be directly converted into the ketone with mineral acid atelevated temperature. Furthermore, the compounds of the general formulaI may be de-sulfurized with a peroxide, for example Na₂ O₂ in analkaline medium to the desired O-compounds I.3,4-Dihydro-2H-isoquinoline-1-thiones may also be oxidized with SeO₂ inalcohol at elevated temperature to the oxygen compounds. Furthermore,the sulfur compounds may also be converted with alkali metalhexacyanoferrate-(III) in ethanol or with silver nitrate in aqueousalcohol into the corresponding oxygen compounds (cf. R. Boudet Bl. /5/,18, 846 (1951)).

As compounds of the invention, there may be prepared, in addition to thecompounds specified in the Examples, preferably also the followingcompounds:

1-(3-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-

1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-

1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-

6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-

6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-

6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-

1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-

1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-

1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-(2-(1-piperidino)-ethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(1-piperidino)-ethyl]-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(chloro-5-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-phenyl-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-phenyl-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(3-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-chloro-3-aminophenyl)-3-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(5-chloro-2-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-5-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(2-chloro-6-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

1-(4-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chloro-3-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(5-chloro-3-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-5-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-6-aminophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chlorophenyl)-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-phenyl-4-[2-(1-phenyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-phenyl-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chloro-3-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(5-chloro-2-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-5-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-6-aminophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1(4-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chloro-3-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1(5-chloro-2-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-3-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-6-aminophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(3-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(4-chloro-3-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(5-chloro-2-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-5-aminophenyl)-4-[2-(thiomorpholinyl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

1-(2-chloro-6-aminophenyl)-4-[2-(thiomorpholinyl)-1,4-dihydro-2H-isoquinoline-3-thione

The compounds of the invention possess valuable therapeutic properties.In addition to other pharmacological properties, they have a favorableaction on the coronary circulation, which is marked especially by ananti-arrhythmic activity. Therefore, the compounds of the invention maybe used in the treatment of disorders of the heart rhythm. Theanti-arrhythmic action was proved on isolated papillary muscles ofGuinea pigs and on strophantine-poisoned dogs.

The novel compounds may be administered alone or in admixture withpharmacologically tolerated carriers. For a form suitable for oraladministration, the active compounds are mixed with known substances andbrought by known methods into forms which are suitable for oraladministration, for example tablets, capsules, aqueous, alcoholic oroily suspensions or aqueous, alcoholic or oily solutions. As inertcarriers, there may be used, for example magnesium carbonate, lactose ormaize starch with addition of other substances, for example magnesiumstearate. Confectioning may be carried out with a dry or wetgranulation. As oily carriers or solvents, there may be used inparticular oils of vegetable or animal origin, for example sunflower oilor cod-liver oil.

A particular form of administration of the compounds of the invention isintravenous administration. For a form suitable for intravenousadministration, the active compounds or their physiologically toleratedsalts together with other known substances are brought into solution.The physiologically tolerated salts are formed, for example with thefollowing acids: hydrochloric acid, hydrobromic acid, hydriodic acid,phosphoric acid, sulfuric acid, methyl-sulfuric acid, amido-sulfonicacid, nitric acid, formic acid, acetic acid, propionic acid, succinicacid, tartaric acid, lactic acid, malonic acid, fumaric acid, citricacid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturicacid, embonic acid, naphthalene-1,5-disulfonic acid, ascorbic acid,phenyl-acetic acid, p-amino-salicylic acid, hydroxy-ethane-sulfonicacid, benzene-sulfonic acid or synthetic resins which contain acidicgroups, for example those having an ion-exchanging action.

As solvents for the corresponding physiologically tolerated salts of theactive compounds to give a form suitable for intravenous administration,there may be used, for example, water, physiological salt solution oralcohols such as ethanol, propanediol or glycerine, furthermore sugarsolutions, for example glucose or mannitose solutions, or also mixturesof the various solvents mentioned.

The single dose for peroral administration is 50 - 500 mg, preferably100 mg, for intravenous or intramuscular administration 20 - 100 mg,preferably 50 mg. The daily dose with peroral administration is 50 -1000 mg, preferably 300 mg, and with intravenous or intramuscularadministration 20 - 500 mg, preferably 100 mg.

The following Examples illustrate the invention:

EXAMPLES 1.1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-3-one

50 ml of 85 % polyphosphoric acid and 50 g of phosphorus pentoxide weremixed with one another and 0.1 mole of2-cyano-1-phenyl-3-(N,N-dimethylaminomethyl)-butane was added at roomtemperature. The reaction mixture was heated to 80°C and 0.04 mole of4-chlorobenzaldehyde was added. The whole was heated for one hour to100°C and 0.04 mole of 4-chlorobenzaldehyde was again added. After afurther hour at 100°C, the reaction mixture was poured into one liter ofwater, adjusted to pH 10 with concentrated ammonia. The crystal magmawas filtered off with suction and recrystallized from ethanol. M.p.253°C.

2. 1-(4-chlorophenyl)-4-[2-(1-pyrrolidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-(1-pyrrolidino)-propane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p. 165°-166°C(HCl salt).

3. 1-(4-chlorophenyl)-4-(2-N,N-diethylaminoethyl)-1,4 -dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-(N,N-diethylamino)-propane and4-chlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 148°-150°C (HCl salt)

4. 1-(4-chlorophenyl)-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-thione

a. 20 millimoles of 1-(4-chlorophenyl)-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-one were introduced into a suspension of20 millimoles of phosphorus pentachloride in 20 ml of toluene and boiledfor 3 hours under reflux.

Then, H₂ S was introduced at room temperature until the development ofHCl ceased.

The solvent was removed under reduced pressure and the residue wasrecrystallized from ethanol. M.p.: 238°-240°C.

b. 20 millimoles of 1-(4-chlorophenyl)-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-1-one were introduced, while stirring, intoa suspension of 8 millimoles of phosphorus penta-sulfide and 32millimoles of calcium oxide in 50 ml of toluene and the whole was heatedfor 15 hours under reflux. The hot toluene solution was poured through afilter to remove the residue and the resin was extracted twice with 50ml portions of benzene. The combined organic solutions were concentratedunder reduced pressure and the remaining oil was recrystallized fromethanol. M.p.: 237°-238°C.

c. 90 millimoles of 1-(4-chlorophenyl)-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-one were dissolved in 35 ml of pyridineand 40 millimoles of phosphorus pentasulfide were added, while stirring.The solution was heated for 4 hours under reflux and, after havingcooled, it was poured into 400 ml of water. The pH value was adjusted to8-8.5 with 10% potassium hydroxide solution and the whole was stirredfor 4 hours. After filtration with suction, the product was washed withwater, dried in air and recrystallized from ethanol. M.p.: 237°-240°C.

5. 1-(4-chlorophenyl)-4-ethyl-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 3-cyano-3-phenyl-5-(1-piperidino)-pentane and 4 -chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 240°-242°C(HCl salt)

6. 1-(4-chlorophenyl)-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-(1-piperidino)-propane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 172°-175°C(HCl salt)

7. 1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-propyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-4-(N,N-dimethylamino)-butane and4-chlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 157°-158°C

8. 1-phenyl-4-[2-(1-pyrrolidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-(1-pyrrolidino)-propane and benzaldehyde in amanner analogous to that described in Example 1. M.p.: 224°-227°C (HClsalt)

9. 1-phenyl-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and benzaldehyde in amanner analogous to that described in Example 1. M.p.: 176°-179°C (HClsalt)

10. 1-(4-chlorophenyl)-4-ethyl-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-one

From 3-cyano-3-phenyl-6-dimethylamino-hexane and 4-chlorobenzaldehyde ina manner analogous to that described in Example 1. M.p.: 156°-159°C.

11. 1-(4-chlorophenyl)-4-ethyl-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 3-cyano-3-phenyl-5-diethylamino-pentane and 4-chlorobenzaldehyde ina manner analogous to that described in Example 1. M.p.: 120°C.

12. 1-(4-chlorophenyl)-4-n-butyl-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-one

From 5-cyano-5-phenyl-8-dimethylamino-octane and 4-chlorobenzaldehyde ina manner analogous to that described in Example 1. M.p.: 170°-172°C.

13. 1-(4-chlorophenyl)-4-n-butyl-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 5-cyano-5-phenyl-7-(1-piperidino)-heptane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 138°-143°C.

14. 1-(4-chlorophenyl)-4-methyl-4-[2-(1-piperidino)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

From 2-cyano-2-phenyl-4-(1-piperidino)-butane and 4-chloro-benzaldehydein a manner analogous to that described in Example 1. M.p.: 193°-196°C

15. 1-(4-chlorophenyl)-4-methyl-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-one

From 2-cyano-2-phenyl-5-dimethylamino-pentane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 227°-229°C.

16. 1-(4-chlorophenyl)-4-methyl-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 2-cyano-2-phenyl-4-diisopropylamino-butane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 112°-114°C.

17. 1-(4-chlorophenyl)-4-methyl-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 2-cyano-2-phenyl-4-diethylamino-butane and 4-chlorobenzaldehyde ina manner analogous to that described in Example 1. M.p.: 122°-123°C.

18. 1-(4-chlorophenyl)-4-(2-N,N-diisopropylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diisopropylamino-propane and4-chlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 202°-205°C (HCl salt)

19. 1-(2-chlorophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and 2-chloro-benzaldehydein a manner analogous to that described in Example 1. M.p.: 100°-103°C(HCl salt)

20. 1-(2,4-dichlorophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and2,4-dichlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 150°-152°C.

21. 1-(4-chlorophenyl)-4-(2-N,N-dimethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-dimethylamino-propane and 4-chlorobenzaldehydein a manner analogous to that described in Example 1. M.p.: 119°-122°C.

22. 1-(4-nitrophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and 4-nitrobenzaldehyde ina manner analogous to that described in Example 1. M.p.: 138°-139°C.

23. 1-(3,4-dichlorophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and3,4-dichlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 133°-137°C.

24. 1-(4-methylphenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-phenyl-3-diethylamino-propane and 4-methylbenzaldehyde ina manner analogous to that described in Example 1. M.p.: 113°-115°C.

25. 1-(4-aminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From the compound of Example 22 by hydrogenation in methanol at 50°C/50atmospheres gauge after 10 hours. M.p.: 245°-248°C (HCl salt)

26. 1-(4-acetylaminophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-dihydro-2H-isoquinoline-3-one

From the compound of Example 25 by acylation in pyridine with aceticanhydride M.p.: 221°-225°C.

27. 1-(4-chlorophenyl)-4-spiro-(4-N-methylpiperidine)-1,4-dihydro-2H-isoquinoline-3-one

From 4-cyano-4-phenyl-N-methylpiperidine and 4-chlorobenzaldehyde in amanner analogous to that described in Example 1. M.p.: 243°C.

28. 1-(4-chlorophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-(3,4-dimethoxyphenyl)-3-diethylaminopropane and4-chlorobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 206°-208°C.

29. 1-phenyl-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-2-(3,4-dimethoxyphenyl)-3-diethylaminopropane andbenzaldehyde in a manner analogous to that described in Example 1. M.p.:169°C.

30.1-(4-nitrophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-(3,4-dimethoxyphenyl)-3-diethylaminopropane and4-nitrobenzaldehyde in a manner analogous to that described inExample 1. M.p.: 212°-213°C.

31.1-(4-pyridyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-1-(3,4-dimethoxyphenyl)-3-diethylaminopropane andpyridine-4-aldehyde in a manner analogous to that described inExample 1. M.p.: 171°-173°C.

32.1-(4-aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From the compound of Example 30 in a manner analogous to that describedin Example 25. M.p.: 183°C (HCl salt)

33. 1-(4-chloro-3-sulfamoylphenyl)-4-(2-N,N-diethylaminoethyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinoline-3-one

From 1-cyano-2-(3,4-dimethoxyphenyl)-3-diethylaminopropane and4-chloro-3-sulfamoylbenzaldehyde in a manner analogous to that describedin Example 1. M.p.: 175°C (HCl salt)

34.1-(4-chlorophenyl)-4-(3-N,N-dimethylaminopropyl)-1,4-dihydro-2H-isoquinoline-3-thione

50 ml of 85 % polyphosphoric acid and 50 g of phosphorus pentoxide weremixed with one another and 0.1 mole of2-phenyl-4-(N,N-dimethylaminomethyl)-pentane-thiocarboxylic acid amidewas added at room temperature. The reaction mixture was heated to 80°Cand 0.04 mole of 4-chlorobenzaldehyde was added. The whole was thenheated for 1 hour to 100°C. Then, 0.04 mole of 4-chlorobenzaldehyde wasadded. After a further hour at 100°C, the reaction mixture was pouredinto 1 liter of water and the pH value was adjusted to 10 by means ofconcentrated ammonia. The crystal magma was filtered off with suctionand recrystallized from ethanol. M.p.: 236-239°C.

35.1-(4-chlorophenyl-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-3-thione

a.N,N'-4-chlorobenzylidene-bis-(2-phenyl-4-dimethylamino-methyl-pentanoicacid thioamide)

0.1 mole of 4-chlorobenzaldehyde and 0.2 mole of2-phenyl-4-dimethylamino-methylpentanoic acid thioamide were kept for3hours at 110°C. After having cooled, the product was recrystallizedfrom ethanol. M.p.: 153°C.

b. 50 ml of 85 % polyphosphoric acid and 50 g of phosphorus pentoxidewere mixed and 0.1 mole of the compound prepared according to Example35a was added at room temperature. The whole was heated for 2 hours to100°C and poured subsequently into 1 liter of water. The pH value wasadjusted to 10 by means of concentrated ammonia. The crystal magma wasfiltered off with suction and recrystallized from ethanol. M.p.237-240°C.

36.1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-3-one

0.02 mole of1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-3-thionewas boiled under reflux for 4 hours with 50 ml of semi-concentratedhydrochloric acid. The reaction mixture was then rendered alkaline,extracted with chloroform and the organic phase was washed once with asolution of sodium bicarbonate and then with water, dried andconcentrated. M.p.:251-255°C.

37.1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-3-one

0.02 mole of1-(4-chlorophenyl)-4-(3-N,N-dimethylamino-2-methyl-propyl)-1,4-dihydro-2H-isoquinoline-1-thionewas dissolved in 50 ml of ethanol and 0.01 mole of selenium dioxide wasadded. The whole was boiled for 4 hours under reflux, cooled,undissolved matter was filtered off and the solution was concentrated.M.p.249°-253°C.

38.1-(4-chlorophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

50 ml of 85 % of polyphosphoric acid and 50 g of phosphorus pentoxidewere mixed and 0.1 mole of 1-cyano-1-phenyl-3-(morpholino-4-yl)-propanewas added at room temperature. The reaction mixture was heated to 80°Cand 0.04 mole of 4-chlorobenzaldehyde was added. The whole was heated to100°C and 0.04 mole of 4-chlorobenzaldehyde was added. After 1 furtherhour at 100°C, the reaction mixture was poured into 1 liter of water.The pH was adjusted to 10 by means of concentrated ammonia. The crystalmagma was filtered off with suction and recrystallized from ethanol.M.p.: 239-245°C (HCl)

39.1-(4-chlorophenyl)-4-[2-(1-methyl-piperazine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one

50 ml of 85 % polyphosphoric acid and 50 g of phosphorus pentoxide weremixed and 0.1 mole of1-cyano-1-phenyl-3-(1-methyl-piperazine-4-yl)-propane was added. Thereaction mixture was heated to 80°C and 0.04 mole of4-chlorobenzaldehyde was added. The whole was heated for 1 hour to 100°Cand 0.04 mole of 4-chlorobenzaldehyde was added. After a further hour at100°C the mixture was poured into 1 liter of water and the pH value wasadjusted to 10 by means of concentrated ammonia. The crystal magma wasfiltered off with suction and recrystallized from ethanol. M.p.:201°-205°C (oxalate)

40.1-(4-chlorophenyl-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-thione

20 millimoles of1-(4-chlorophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-onewere introduced, while stirring, into a suspension of 8 millimoles ofphosphorus pentasulfide and 32 millimoles of calcium oxide in 50 ml oftoluene and the whole was heated for 7 hours under reflux until thereaction was completed. The reaction mixture was decanted off to removethe resinous residue and extracted twice with toluene. The combinedorganic solutions were concentrated and the product was recrystallizedfrom isopropanol. M.p.: 228°-231°C (HCl)

We claim:
 1. A 1,4-dihydro-2H-isoquinoline compound of the formula ##SPC21##and physiologically tolerated salts thereof, wherein R¹ is hydrogen or straight-chain or branched alkyl of 1 to 6 carbon atoms; R² is di-lower alkyl-amino-lower alkyl wherein the alkyl groups of the dialkylamino group may also form a piperidine or pyrrolidine ring with the nitrogen atom to which they are attached; R³ is pyridyl, phenyl, or phenyl mono- or di- substituted by halo, nitro, amino, alkanoylamino having 1 to 4 carbon atoms or alkyl having 1 to 4 carbon atoms; R⁴ and R⁵, which may be the same or different, are hydrogen or alkoxy having 1 to 4 carbon atoms; and X is oxygen or sulfur.
 2. 1-(4-Aminophenyl)-4-(2-N,N-diethylaminoethyl)-6,7-di-methoxy-1,4-dihydro-2H-isoquinoline-3one.
 3. 1-(4-Chlorophenyl)-4-(2-N,N-diethylaminoethyl)-1,4-di-hydro-2H-isoquinoline-3-one. 